The brain consists of a plurality of neurons that communicate with each other via chemical messengers. Each neuron generates neurochemicals, called neurotransmitters, which act at receptors on the cellular membranes of neurons.
One group of neurotransmitters, the monoamine neurotransmitters, includes dopamine (DA), serotonin (5-HT) and norepinephrine (NE).
These monoamine neurotransmitters are released into the synaptic cleft in order to stimulate post-synaptic receptor activity. Removal or inactivation of monoamine neurotransmitters occurs mainly by a re-uptake mechanism into presynaptic terminals, which terminates monoaminergic transmission. Blocking or inhibiting the re-uptake increases the synaptic availability of the neurotransmitters, thereby potentiating the signal (Kitama et al., 1996, Jpn. J. Pharmacol. 72:195-208).
Inhibition of monoamine neurotransmitter re-uptake has been exploited to develop treatments for a large number of neurological disorders. For example, the selective dopamine transporter (DAT) antagonist benztropine is used clinically for the treatment of Parkinson's disease (Agoston et al., 1994, J. Med. Chem. 40:4329-4339) and methylphenidate (Ritalin.RTM.; CebaGeneva) is used to treat attention deficit hyperactivity disorder (Klein, 1995, Arch. Gen. Psychiatry 52:429-433).
Norepinephrine transporter (NET) re-uptake inhibitors such as desipramine, nortriptyline and protriptyline, and the mixed serotonin and norepinephrine re-uptake inhibitors imipramine and amitriptyline exhibit effective antidepressant activity (Thomas et al., 1987 Psychopharmacol. 93:193-200). However, they also exhibit a high incidence of adverse side effects (Blackwell, 1981, Drugs 21:201-219).
Serotonin-selective re-uptake inhibitors are thought to exhibit fewer side effects than the other classes of monoamine re-uptake inhibitors. The selective serotonin transporter (5-HTT) antagonists fluoxetine (Prozac.RTM.; Dista) and paroxetine (Paxil.RTM.) are used for the treatment of depression and related psychological disorders with significantly fewer side effects than other treatments (Wong et al., 1995, Life Sci. 57:411-441; Dechant et al., 1991, Drugs 41:225-253; Moller et al., 1996, Drugs 52:625-638). Other serotonin selective re-uptake inhibitors currently used to treat depression include citalopram, fluvoxamine, sertraline, nefazadone and tianeptine (Thakore et al., 1996, J. Serotonin Res. 3:145-160). These serotonin-selective re-uptake inhibitors also exhibit fewer side effects than the classical tricyclic antidepressants which are norepinephrine re-uptake inhibitors (see, Moller et al., supra). Venlafaxine, which is a dual serotonin and norepinephrine re-uptake inhibitor (with a five-fold selectivity for serotonin) also exhibits a side effect profile that is similar to the other serotonin-selective re-uptake inhibitors.
However, while the serotonin-selective re-uptake inhibitors induce fewer adverse side effects than the other classes of monoamine neurotransmitter inhibitors, they still cause sleep and gastrointestinal disturbances, as well as sexual dysfunction. Thus, new classes of clinically useful serotonin-selective re-uptake inhibitors which reduce these and other side effects would be highly desirable.
Serotonin-selective re-uptake inhibitors inhibit the serotonin transporter within minutes; however, with the exception of venlafaxine (4-7 days; Preskorn, 1994, J. Clinical Psychiatry 55 (Suppl. A):6-22) and citalopram, their full antidepressant effect is observed only after three to four weeks of treatment, indicating that re-uptake inhibition per se is not necessarily fully responsible for their anti-depressant response. Rather, further activities probably underlie their therapeutic effect. This delayed onset of anti-depressant effect is considered to be a serious drawback to current serotonin-selective re-uptake inhibitor therapeutics. As inhibition of dopamine re-uptake has been implicated in providing a more rapid onset of anti-depressant effect, development of new classes of serotonin-specific re-uptake inhibitors which also exhibit low to moderate dopamine re-uptake inhibition would be highly desirable.
Cocaine, one of the most commonly abused addictive drugs in America, also potently inhibits all three monoamine transporters. A growing body of evidence points to the ability of cocaine to bind to the DAT and to inhibit re-uptake of dopamine as being responsible for the reinforcing properties of this drug (Volkow et al., 1997, Nature 6627:830-833). However, evidence suggest 5-HTT inhibition also plays a modulatory role in cocaine's reinforcing properties (Walsh et al., 1997, Psychopharmacol. 130:41-58). A number of highly potent cocaine analogs which exhibit varying degrees of selectivity for the monoamine transporters, and information concerning their structure-activity relationships, have been reported (Clarke et al., 1973, J. Med. Chem. 16:1260-1267; Abraham et al., 1992, J. Med. Chem. 35:141-144; Kozikowski et al., 1994, J. Med. Chem. 37:3440-3442; Stoelwinder et al., 1994, Biorg. Med. Chem. Lett. 4(2):303-308). While the precise details of the binding interactions between these compounds and the various transporters are not well understood (Carroll et al., 1991, J. Med. Chem. 34:2713-2725; Carroll et al., 1993, In: Drug Design For Neuroscience, Kozikowski, Ed., Raven Press: New York, pp. 149-166), except for a small number of recently reported compounds (see, Madras et al., 1996, Synapse 24:340-348), all contain the common structural features of a phenyl group and a basic amine.
Despite these common features and the existence of a proposed pharmacophore model (Froimowitz, 1993, J. Comput. Chem. 14:934-943), little is known about the structural requirements underlying monoamine transporter selectivity. Given the different therapeutic effects exhibited by the various classes of selective monoamine transporter antagonists, the ability to develop new classes of monoamine re-uptake inhibitors showing varying degrees of specificity for the three monoamine transporters would be highly desirable. In particular, the ability to design and synthesize monoamine transporter agonists with specified selectivities for certain of the transporters would allow the development of new classes of therapeutics specifically tailored to treat disorders associated with certain of the transporters, while at the same time minimizing any undesirable side effects. Accordingly, these are objects of the present invention.